Although modern vaccines and drugs are effective in controlling disease, there are serious problems with parenteral injections. The use of the standard hollow metal needle attached to a syringe is inherently cumbersome. The usual process of giving an injection involves performing all the following steps using sterile technique:
1. Take the freeze-dried drug, in its rubber-capped glass vial, from the refrigerator and remove the sterile cap. PA1 2. Take and prepare a similar vial of sterile water for injection (WFI) from its box. PA1 3. Remove a wide-bore needle from its sterile packaging. PA1 4. Remove a sterile disposable syringe from its sterile packaging. PA1 5. Attach the needle to the syringe. PA1 6. Use the syringe and needle to aspirate a precise volume of sterile WFI. PA1 7. Use the syringe and needle to deliver this WFI into the vial containing the freeze-dried drug. PA1 8. Swirl or shake the vial until the dried drug is completely dissolved. PA1 9. Use the syringe and needle to aspirate the required dose back into the syringe. PA1 10. Remove a narrow bore needle from its sterile packaging. PA1 11. Replace the used wide bore needle used in 5-9 above with the fresh narrow bore needle for injection. PA1 12. Carefully expel all the air from the syringe and needle. PA1 13. Inject the drug.
This tedious process can only be reliably undertaken by medically trained personnel. The risks of incorrect dilution or dose measurement are obvious. Any failure of sterile technique can lead to dangerous infections. The danger is greater if the reconstituted drug or vaccine is stored for any length of time before it is used. The final injection step also requires training and practice to achieve the correct depth and the dexterity to deliver the injection quickly and with minimal pain. These skills are not in abundant supply. The lack of trained personnel actually constrains current, immunization campaigns.
Most syringes and needles today are designed to be disposable. However, such disposable syringes are in fact routinely re-used, both in the developing world and by drug addicts in the developed world. Typically the cleaning and sterilization techniques used are inadequate, leading to serious risks of infection and cross-contamination.
An additional problem with parenteral injections is that only a few drugs or vaccines are available in the form of injection-ready, stable liquids. The great majority of parenteral preparations are freeze-dried and require dilution before injection. The great majority also require constant refrigeration during storage.
Patient compliance with immunization protocols is also a serious difficulty faced by public health authorities. When standard syringes and needles are used, patients often do not return to field stations for follow-up doses. This is particularly true for infants, who must undergo a series of injections. Injections are perceived by patients as very painful, though in actuality the pain experienced during insertion of a properly sharp and well lubricated needle is not very severe. Much of the perceived pain is actually anxiety, caused by the sight of the needle, especially as it enters the flesh. This can be so severe as to cause patients to fail to complete a course of immunization.
Present needle technology also present problems for health workers, who are at risk from infection due to accidental needle sticks. When improperly discarded, conventional needles and syringes also present a health hazard to the local population.
Present parenteral injection technology has recently been deemed by the World Health Organization (WHO) to be incompatible with their requirements for the planned Global Programme of Vaccination and Immunization (GPV) initiatives. It is estimated that 6 additional parenteral vaccines will be recommended for childhood vaccination by the year 2005, requiring a total of 3.6 billion immunization injections per year. The total number of parenteral injections, including injected drugs as well as vaccines, will be roughly ten times this number. Major health care providers such as UNICEF, the WHO and CDC have recently confirmed that a radical new technology is required that can be used by personnel with minimal training and that is safer, more convenient, and more comfortable than the syringe and needle. (Jodar L., Aguado T., Lloyd J. and Lambert P-H,(1998) Revolutionizing Immunizations Gen. Eng. News 18, p. 6.) The criteria required by the WHO for the next generation of vaccines are: Heat stability, no cold chain of refrigerators; affordable; zero risk of cross infection; individual injection devices and vaccine doses packaged together; simple and easy to use; easy and safe disposal; no wastage; minimal discomfort; and minimum volume.
It is known to package parenteral medications in disposable, single dose delivery devices. On approach is to package single doses of vaccines in simple plastic blisters or collapsible tubes with an integral hypodermic needle attached. Examples are disclosed in U.S. Pat. Nos. 4,013,073 to Cunningham and 4,018,222 to McAleer et al. The Uniject.TM. plastic blister device (Becton Dickinson and Co.) is another example. Known single-use injectors require medical expertise to use and are intimidating because of the naked needle.
Some single-use injectors are designed to self-destruct, eliminating the temptation to re-use. Examples are disclosed in U.S. Pat. Nos. 3,998,224 to Chiquiar-Arias, 4,233,975 to Yerman, and 4,391,272 to Staempfli. Another example is the Soloshot.TM. syringe (manufactured by Becton Dickinson). These syringes are more expensive than standard syringes, and also require medical expertise to use.
The use of breakable tabs and snap rings in plastic containers, such as bottles, is well known. These devices are commonly used for tamper protection, sealing, and the like. An early example is disclosed in U.S. Pat. No. 3,407,956 to Linkletter, which shows a removable and replaceable bottle cap. The plastic cap has an annular beaded molded on the inside, which overrides a similar bead molded on the outside of the neck of the bottle. Natural elasticity of the materials used in manufacturing the cap permit it to expand temporarily. This allows the beads to override and then to contract again immediately once the beads have passed each other. This seats the cap firmly on the container and provides a good seal.
Needleless injectors are well known. These injectors use a fine stream of pressurized liquid to penetrate the skin. The pain is considerably less than that experienced during a conventional injection. Early designs used high pressure throughout the injection. Later, it was realized that high pressure was required only at the start of the injection, to punch a hole through the tough epidermis. The bulk of the injection could then be infused along the initial track under much lower pressure. U.S. Pat. No. 2,704,542 to Scherer and 3,908,651 to Fudge disclose examples of this design. The engineering demands of changing the pressure during the injection and resulting complexity have limited the use of such injectors.
Standard high-pressure needleless jet injectors are also inherently complex, requiring precision engineering with dozens of machined steel parts. Most designs have focused on the production of robust, reliable, heavy-duty machines capable of many injections at high rates for mass immunization campaigns. Infection due to cross-contamination in such jet injectors has been reported. This may be due to the high pressures caused in the tissues. As the distended tissue relaxes and the pressure simultaneously falls in the injector, liquid can be sucked into the injector. This liquid may be contaminated with blood or interstitial fluid. This problem has been addressed by the development of single-use vials which insert into the jet injector. This approach may be combined with a replaceable nozzle and a vaccine fluid path of cheap plastic, as disclosed in U.S. Pat. 4,266,541 to Landau.
A mono-dose disposable jet injector has been developed under the trademark "Intraject" by Weston Medical, UK. Similar to other jet injectors, this injector uses a highly compressed gas in a canister to propel the vaccine dose. See Lloyd J. S., Aguado M. T., Pre-Filled Monodose Injection Devices: A safety standard for new vaccines, or a revolution in the delivery of immunizations?, Global Programme on Vaccines and Immunization, World Health Organization, May 1998.
It is known that extraordinary stability can be conferred on very labile biomolecules by drying them in glasses formed from certain sugars. Trehalose is one example. See U.S. Pat. No. 4,891,319 to Roser, and Colaco C., Sen S., Thangavelu M., Pinder S., and Roser, B. J., Extraordinary stability of enzymes dried in trehalose: Simplified molecular biology. Biotechnol. 10 1007-1011 (1992). A similar technique can be applied to stabilized vaccines. See Gribbon E. M., Sen S., Roser B. J. and Kampinga J., Stabilisation of Vaccines Using Trehalose (Q-T4) Technology, in F. Brown, (ed) New Approaches to Stabilisation of Vaccine Potency Dev Biol Stand Basel Karger 87 193-199 (1996).
A more recent development in glass-forming preparations using sugar derivatives is stabilization brought about by the active biomolecules remaining in solid solution in the "solid solvent" phase of the glass matrix. The biomolecules are stable because of the extremely high viscosity of the inert glass. Molecular diffusion and molecular motion are negligible in these solid solutions. Chemical reactions, which depend on the reactive species being free to diffuse together, are therefore non-existent. Providing the glass itself is chemically non-reactive and dry, the product typically remains stable at temperatures up to the softening point of the glass. This is often expressed as the "glass-transition temperature" or Tg. Only as the glass begins to soften and melt can molecular diffusion and hence degradation start.. Even at temperatures above the Tg, it takes a certain time for damage to occur and the rate of deterioration is slow because the viscosity of even the softened glass is high. Because degradation reactions are chemical processes with typical kinetics, the determining factor in product damage is actually a mathematical product of the elevated temperature and the time of exposure rather than just the high temperature. Even fragile compounds in these glasses can be briefly exposed to high temperatures with insignificant damage. While sugar glasses have advantages in stability over conventional parenteral preparations, the other difficulties of conventional parenteral injection remain, such as dose mismeasurement, pain, and infection risk.
Phosphate glasses are also suitable for stabilization of parenteral medications. See U.S. Pat. No. 4,698,318 to Vogel et al. Phosphate glasses are typically much stronger than sugar glasses. Because of their strength, phosphate glasses are often used as structural elements in bone repair. Mixtures of metal carboxylates such as the acetate salts of sodium, potassium, calcium and zinc also form excellent glasses, PCT Publication No WO90/11756). By using different mixtures of the individual carboxylates and by using different metal cations, it is possible to tailor these phosphate and carboxylate glasses to dissolve at different, specific rates in body fluids. Being composed of simple chemicals normally prevalent in the body, phosphate and carboxylate glasses exhibit very low toxicity. The major disadvantage of these glasses is the high temperature needed to melt them. This precluded most drugs being incorporated in the glass in solid solution, and restricted their use to pre-formed hollow tubes which were loaded with stable powdered drugs. See U.S. Pat. Nos. 4,793,997 and 4,866,097 to Drake et al. Because it is difficult to fill narrow tubes with dry powders, phosphate glass tubes are generally of large diameter. Large diameter tubes are traumatic to inject and suitable only for veterinary applications.
One approach to the problem of filling narrow tubes with powdered actives is to suspend the powdered drug or vaccine in a non-aqueous liquid in which it is insoluble. These suspensions flow more readily into fine capillary tubes and carry the powdered active with them. Many organic solvents such as ethanol, acetone, dichloromethane, chloroform, and toluene etc. may be used. However, many of these industrial solvents can react destructively with biological molecules. This difficulty can be avoided by first enclosing the actives in stabilizing sugar glasses, as disclosed in U.S. Pat. No. 5,589,167 to Cleland et al. and in Gnbbon E., Hatley R, Gard T., Blair J., Kampinga J. and Roser B. Q-T4 Stabilisation and novel drug delivery formats, Conf. Report Amer. Assoc. Pharm. Soc., 10th annual meeting, Miami Beach, Fla. (1995),